Semliki Forest virus (SFV) is a neurotropic virus that induces paralysis in B6 mice and leads to late demyelinating lesions. This demyelination, which occurs in the absence of persisting virus in the brains and spinal cords of mice, is immune-mediated. SFV-infection of mice has been used as a model to study the pathogenesis of multiple sclerosis (MS). Using this model, we have suggested that the effector mechanism in the induction of white matter injury (demyelination) is mediated by antibodies to myelin peptides(s) that are triggered by SFV-infection. We have previously found that immunization of B6 mice with a peptide of SFV that has homology (molecular mimicry) with a peptide of myelin oligodendrocyte glycoprotein (MOG) induced cross-reactive T cell and antibody responses to a MOG peptide and a late-onset neurological disease with minimal CNS inflammation and extensive demyelinating lesions. Moreover, unlike SFV-infected wild-type (WT) mice, B-cell-/- mice did not exhibit demyelination. Based on these observations we have proposed that 1) The initial inflammatory cells give rise to autoreactive helper T cells and maturation of resident B cells that secrete pathogenic antibodies, that activate the microglia and induce late demyelination, using FACS and histological studies of various appropriate knock-out (KO) mice. 2) The specificity of the immunopathogenic T cell and antibody response in SFV-infected animals will be investigated. Specifically, the appearance of CD4+ T cells responding to SFV epitopes (and cross reactive with selected mimicked myelin peptides), and to MOG and MBP proteins and peptides, in the blood and CNS of SFV-infected animals, will be studied. Specific hypothesis to be tested is that these T cells give rise to corresponding antibodies which are the effector mechanism in demyelination. 3) The cell type that can restore demyelination in the KO mice will be investigated. The specific hypothesis to be tested in this aim is that demyelinating activity will be restored only if functional B cells are present. 4) The ultimate role of antibody in the induction of autoimmune mediated demyelination will be completed by using transgenic mice with B cells that secrete antibody to SFV E2-mimicked, myelin peptides. Specific hypothesis to be tested is that when these mice spontaneously release these antibodies (separately or combined) into the CNS, demyelinating lesions will appear.